Targeted degradation of hexokinase 2 for anti‑inflammatory treatment in acute lung injury

Yang,Jiayan; Dong,Liangliang; Wang,Yifan; Gong,Lifen; Gao,Hongwei; Xie,Yicheng

doi:10.3892/mmr.2024.13206

Targeted degradation of hexokinase 2 for anti‑inflammatory treatment in acute lung injury

Authors:
- Jiayan Yang
- Liangliang Dong
- Yifan Wang
- Lifen Gong
- Hongwei Gao
- Yicheng Xie
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Affiliations: College of Pharmacy, Guangxi University of Chinese Medicine, Nanning, Guangxi Zhuang Autonomous Region 530000, P.R. China, Department of Pulmonology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China, Department of Pulmonology, Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310052, P.R. China
Published online on: March 19, 2024 https://doi.org/10.3892/mmr.2024.13206
Article Number: 83
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Acute lung injury (ALI) is an acute inflammatory lung disease associated with both innate and adaptive immune responses. Hexokinase 2 (HK2) is specifically highly expressed in numerous types of inflammation‑related diseases and models. In the present study in vitro and in vivo effects of targeted degradation of HK2 on ALI were explored. The degradation of HK2 by the targeting peptide TAT (transactivator of transcription protein of HIV‑1)‑ataxin 1 (ATXN1)‑chaperone‑mediated autophagy‑targeting motif (CTM) was demonstrated by ELISA and western blotting in vitro and in vivo. The inhibitory effects of TAT‑ATXN1‑CTM on lipopolysaccharide (LPS)‑induced inflammatory responses were examined using ELISAs. The therapeutic effects of TAT‑ATXN1‑CTM on LPS‑induced ALI were examined via histological examination and ELISAs in mice. 10 µM TAT‑ATXN1‑CTM administration decreased HK2 protein expression and the secretion of proinflammatory cytokines (TNF‑α and IL‑1β) without altering HK2 mRNA expression in LPS‑treated both in vitro and in vivo, while pathological lung tissue damage and the accumulation of leukocytes, neutrophils, macrophages and lymphocytes in ALI were also significantly suppressed by 10 µM TAT‑ATXN1‑CTM treatment. TAT‑ATXN1‑CTM exhibited anti‑inflammatory activity in vitro and decreased the severity of ALI in vivo. HK2 degradation may represent a novel therapeutic approach for ALI.

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